The stability of bone implants depends greatly on their ingrowth properties. For dental implants to work, there must be sufficient bone in the jaw, and the bone has to be strong enough to hold and support the implant. Where there is insufficient or inadequate maxillary or mandibular bone in terms of depth or thickness, grafts are used in prosthetic dentistry to provide secure integration with the dental implant. Conventional grafts include the patient's own bone (autografts), processed bone from cadaver (allografts); bovine bone or coral (xenografts); and synthetic bone-like or bone-mimetic materials.
In a typical procedure, the dentist or oral surgeon creates a large flap of the gingiva or gum to expose the jawbone at the graft site, installs some types of block and onlay grafts in and on existing bone and finally takes measures to repel unwanted infections. The gingiva is then sutured over the site and the graft site allowed to heal for several weeks or months. The healing involves a complicate cascade of adaptive cellular responses such as differentiation, migration, attachment, proliferation, extracellular matrix synthesis and finally mineralization. The osteointegration of the graft or implant into the surrounding bone is however poorly understood. Osteoinduction and osteogenesis involve a plethora of growth factors and there are numerous further molecules which are said to contribute to these processes.
The bone morphogenic proteins (BMP) are the only growth factors known to induce bone formation heterotopically. Supplementary doses of BMPs boost the bone healing by inducing undifferentiated mesenchymal cells to differentiate into osteoblasts. Bone grafts and implants however shall result in a live vascular bone which is very much like natural. U.S. Pat. No. 5,478,237 (Ishikawa) discloses an implant coated with a layer of hydroxyapatite, WO 02/078759 (Stratec Medical AG) an implant having a layer of a porous metal oxide comprising amorphous and nanocrystalline calcium phosphate and hydroxyapatite, WO 02/085250 (KERAMED GmbH) an implant wherein a coating of resorbable calcium phosphate phases contains adhesion and signal proteins such as bone sialoprotein (BSP), bone morphogenic protein (BMP), fibronectin, osteopontin (OPN), ICAM-1, VCAM and derivatives thereof. Further grafts and implants of this type are described in EP 1 166 804 A2 (Merck, Darmstadt) and WO 99/08730 (Children's Medical Center Corporation). DE 100 37 850 A1 (Jenissen H) and WO 03/059407 A1 (Straumann Holding AG) describe grafts and implants treated with ubiquitin or transforming growth factor (TGF) or systemic hormones such as osteostatin, osteogenie and osteogrowth peptide (OGP). U.S. Pat. No. 7,229,545 B2 (Biomet Deutschland GmbH) teaches bone-analogous coatings made of a collagen matrix mineralised with calcium phosphate, EP 1 442 755 A1 (Depuy Products) a bioactive ceramic coating comprising osteogenic proteins OP-1, BMP-7 and non-collagenous bone matrix proteins. Osteogenic activities have further been reported for fibroblast growth factor (FGF), transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), insulin growth factor (IGF) and family members of the foregoing.
WO 2005/104988 (Armbruster et al) claims implants and bone repair matrices treated with an underglycosylated human rBSP. The implants are made of titanium, zirconium, ceramic, metal alloys or stainless steel and may be coated with amorphous or crystalline hydroxyapatite and/or calciumphosphate. Such bone-mimetic coatings however suffer from the disadvantage that they tend to loosen from the substrate with time which affects the long-term stability of implants.
WO 03/047646 (Inion Ltd., Tampere, Finland) teaches bone grafts that can be fashioned into medical implants. The graft or implant is made of a base material comprising a matrix of resorbable polymers or copolymers, and N-methyl-2-pyrrolidone (NMP). Reichhardt et al describe in European Cells and Materials 2006, 11(2):27f a bio-composite comprising granules of beta-tricalcium phosphate (beta-TCP) coated with a copolymer of polyglycolic and polylactic acid. The biocomposite can be made moldable for placement by mixing it with N-methyl-pyrrolidone. Nair et al disclose in J. Biomater. Appl. 2006, 20:307-24 dental grafts and implants wherein the beta-TCP granules are held together by thermal fusion of a polyglycolic-polylactic acid copolymer. The beta-TCP particles are described as inhibiting the differentiation and proliferation of mesenchymal stem cells to osteoblasts and osseous healing. Wang et al. describe in J. Orth. Res., 2002, 20:1175ff such a kind of inhibition too for metal abrasion particles as well as for worked and large surface areas.
U.S. Pat. No. 6,458,763 (Peterson et al.) claims a bioactive composition for the repair of damaged or diseased bone and cartilage. The bioactive composition is administered via a delivery vehicle comprising a pharmaceutically acceptable basis and physiological mineral fillers such as tricalcium phosphate, hydroxyapatite, gypsum and the like. When a hole is drilled into the rat calvaria at or adjacent the parietal eminence and the bioactive composition pumped to the site of the calvarial defect over a period of 14 days using an osmotic pump, then there is observed an in vivo induction of bone tissue growth around the drilled hole. The method of administration and the composition are clearly not suitable for prosthetic dentistry.
WO 94/13310 (Höök et al) claims a composition comprising as active ingredient a competitor peptide which seems to fight the attachment of Staphylococcus aureus to bone tissue as well as osteomyelitis (Ryden et al., 1989, Eur. J. Biochem. 184: 331f).
The prior art notwithstanding represents a problem as dental implants often give rise to a periodontal condition called peri-implantitis caused by an infection introduced during surgery or a failure by the patient to follow correct oral hygiene routines. While implantitis can be dealt with by a course of antibiotics and special oral rinses in the days prior and past surgery, a pre-emptive treatment of peri-implantitis as well as improved wound and soft tissue healing would be more desirable. Aseptic loosening, inflammation reactions and long-term stability of endosseous implants further continue to remain a problem. Despite bioactive coatings there is still a considerable period of time between surgery and osteointegration until when bone grafts and endosseous tooth implants can withstand typical pressure, shear and tensile forces.
It is in particular an object of the instant invention to provide a graft material which allows easy placement as well as methods and compositions for furthering the healing of bone and soft tissue lesions in the course of prosthetic dentistry.